Fludarabine Monophosphate Followed by Iodine-131 Tositumomab Fludarabine Monophosphate Followed by Iodine-131 Tositumomab (NHL)

directed against the CD20 antigen, is effective in the treatment of
previously untreated, as well as relapsed and refractory, low-grade
and transformed, low-grade non-Hodgkins lymphoma (NHL).
Fludarabine (Fludara) is also active as a single agent or in
combination in NHL. In vitro data have shown that iodine-131
tositumomab and fludarabine have a markedly supraadditive effect on
tumor cell killing.

We are evaluating the safety and efficacy of a sequential regimen of
three cycles of fludarabine (25 mg/m² × 5 d q5wk) followed,
6 to 8 weeks later, by tositumomab and iodine-131 tositumomab for
patients with previously untreated, low-grade, transformed, low-grade
or follicular NHL. A total of 38 patients were enrolled, 14 of whom
are evaluable for response at least 3 months post-treatment with
iodine-131 tositumomab. Baseline patient characteristics (N = 14)
were: median age, 52.5 years, > 60 years old (2 patients), male (7
patients), median time from diagnosis (2 months), and stage at time
of treatment (stage II, 1 patient; stage IV, 13 patients).

Patients received a single dosimetric dose (450 mg of tositumomab
intravenously [IV] followed by 35 mg [5 mCi] of iodine-131
tositumomab over 20 minutes) and then had three whole-body counts
obtained over the next 7 days. The whole body counts were used to
calculate the required activity (mCi) to deliver the desired
therapeutic dose

(65 cGy for platelet counts of 100,000 to 149,000 cells/mm³ and
75 cGy for platelets ³ 150,000
cells/mm³). The single therapeutic dose (450 mg of tositumomab
IV followed by 35 mg of tositumomab containing an appropriate amount
of activity [mCi] of iodine-131 to deliver the specified total-body
dose [cGy] over 20 minutes) was administered 7 to 14 days after the
dosimetric dose.

The toxicity following fludarabine was mainly hematologic. The
principal toxicity following iodine-131 tositumomab was also
hematologic: absolute neutrophil count (ANC) was < 500
cells/mm³ in five patients (36%); platelet count was < 10,000 cells/mm³
in one patient (7%). Nonhematologic toxicity was typically mild to
moderate; the most frequent events were nausea, asthenia, headache,
increased cough, and rhinitis. One patient developed antimurine
antibodies (HAMA).

An investigator-assessed response was seen in 13 of 14 patients (93%;
2 complete responses [CRs], 11 partial responses [PRs]) after
fludarabine. At 25 weeks after treatment with iodine-131 tositumomab,
14 (100%) of 14 patients had achieved a response (10 CRs [71%], 4
PRs). Of the 11 PRs after fludarabine, 7 converted to CRs after
iodine-131 tositumomab. One patient with stable disease after
fludarabine converted to a CR. Three patients have developed
progressive disease. Only one patient required a reduction in the
fludarabine dosage.

CONCLUSIONS: Fludarabine, followed by tositumomab and iodine-131
tositumomab, can be safely administered to patients. The
immunosuppressive effects of fludarabine limit the seroconversion to
HAMA positivity in patients receiving tositumomab and iodine-131
tositumomab. The efficacy of tositumomab and iodine-131 tositumomab
appears to augment that of fludarabine, improving overall responses
and CRs. All treated and evaluated patients exhibited a response
during the study. Additional patients have been treated and will be assessed.